Project 1 Abstract: The project seeks a robust and scalable procedure for preparation of clinically-translatable long-acting reservoir-targeted nanoformulations of antiretroviral therapy (nanoART) with optimal size range, surface coating and colloidal stability. We will, first, develop prodrugs (from what is presently hydrophilic to hydrophobic ART) with a range of viral action sites then optimize the formulation functional parameters (manufacturing methods, drug loading, particle size and colloidal stability) to facilitate drug uptake by monocyte-macrophages for sustained therapeutic drug concentrations in cells over an extended time period. The development of indoleamine 2,3-dioxygenase inhibitors to facilitate elimination of restricted viral infection would provide a stage for viral education strategies to be initiated. Second, we will develop versatile synthetic procedures for conjugation of targeting ligands to coating polymers to facilitate decorations of nanoART to cellular HIV reservoirs. Third, we will determine whether the modifications developed in aims 1 and 2 will translate into improve pharmacokinetic profiles. We posit that harnessing of monocyte-macrophages as cell carriers and depots will enhance antiretroviral delivery across tissue barriers and into sites of viral growth. The drug's synergistic long-acting antiretroviral efficacy will be determined in cell culture assays and validated in animals (in collaboration with Projects 2, H. Gendelman and 3, M. Boska; Core C, L. Poluektova and H. Fox).